Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. Despite maximal therapy consisting of surgery and radio/chemotherapy, GBM remains largely incurable with a median survival of less than 15 months. GBM has a strong immunosuppressive nature with a multitude of tumor and microenvironment (TME) derived factors that prohibit an effective immune response. To date, all clinical trials failed to provide lasting clinical efficacy, despite the relatively high success rates of preclinical studies to show effectivity of immunotherapy. Various factors may explain this discrepancy, including the inability of a single mouse model to fully recapitulate the complexity and heterogeneity of GBM. It is therefore critical to understand the features and limitations of each model, which should probably be combined to grab the full spectrum of the disease. In this review, we summarize the available knowledge concerning immune composition, stem cell characteristics and response to standard-of-care and immunotherapeutics for the most commonly available immunocompetent mouse models of GBM.

The role of the innate immune system in ovarian cancer is gaining importance. The relevance of tumor-associated macrophages (TAM) is insufficiently understood. In this pilot project, comprising the immunofluorescent staining of 30 biopsies taken from 24 patients with ovarian cancer, we evaluated the presence of total TAM (cluster of differentiation (CD) 68 expression), M1 (major histocompatibility complex (MHC) II expression), and M2 (anti-mannose receptor C type 1 (MRC1) expression), and the blood vessel diameter. We observed a high M1/M2 ratio in low-grade ovarian cancer compared to high-grade tumors, more total TAM and M2 in metastatic biopsies, and a further increase in total TAM and M2 at interval debulking, without beneficial effects of bevacizumab. The blood vessel diameter was indicative for M2 tumor infiltration (Spearman correlation coefficient of 0.65). These data mainly reveal an immune beneficial environment in low-grade ovarian cancer in contrast to high-grade serous ovarian cancer, where immune suppression is not altered by neoadjuvant therapy.

In monotherapy, immunotherapy has a poor success rate in ovarian cancer. Upgrading to a successful combinatorial immunotherapy treatment implies knowledge of the immune changes that are induced by chemotherapy and surgery. Methodology: Patients with a new d ovarian cancer diagnosis underwent longitudinal blood samples at different time points during primary treatment. Results.: Ninety patients were included in the study (33% primary debulking surgery (PDS) with adjuvant chemotherapy (ACT), 61% neo-adjuvant chemotherapy (NACT) with interval debulking surgery (IDS), and 6% debulking surgery only). Reductions in immunosuppression were observed after NACT, but surgery reverted this effect. The immune-related proteins showed a pronounced decrease in immune stimulation and immunosuppression when primary treatment was completed. NACT with IDS leads to a transient amelioration of the immune microenvironment compared to PDS with ACT. Conclusion: The implementation of immunotherapy in the primary treatment schedule of ovarian cancer cannot be induced blindly. Carboplatin–paclitaxel seems to ameliorate the hostile immune microenvironment in ovarian cancer, which is less pronounced at the end of primary treatment. This prospective study during primary therapy for ovarian cancer that also looks at the evolution of immune-related proteins provides us with an insight into the temporary windows of opportunity in which to introduce immunotherapy during primary treatment.

Novel treatment strategies are needed to provide a better prognosis for ovarian cancer. For this purpose, the current study was designed to evaluate the effects of different types of particle drug carriers on tumor response and on the tumor immune microenvironment (TME) after intraperitoneal (IP) administration in a murine tumor model. Mice with ID8-fLuc ovarian cancer were injected IP with pegylated liposomes, hydroxyapatite, polystyrene, poly(lactic-co-glycolic acid) (PLGA) and calcium carbonate (CaCO₃) microparticles to evaluate the effect of the candidate carriers without drugs. Our results show that several types of microparticle drug carriers caused hyperproliferation of the tumor when injected IP, as reflected in a reduced survival or an accelerated onset of ascites. Alterations of the product formulation of CaCO₃ microparticles could result in less hyperproliferation. The hyperproliferation caused by CaCO₃ and PLGA was largely driven by a strong innate immune suppression. A combination with chemotherapy was not able to sufficiently counteract the tumor progression caused by the drug carriers. This research points towards the importance of evaluating a drug carrier before using it in a therapeutic setting, since drug carriers themselves can detrimentally influence tumor progression and immune status of the TME. However, it remains to be determined whether the hyperproliferation in this model will be of relevance in other cancer models or in humans.

Objective Ovarian cancer remains the fifth leading cause of cancer-related deaths in women. The immune system influences the onset and progression of ovarian cancer. Therefore, we aimed to study the behavior of ovarian cancer in patients with a pre-existing immune dysfunction, more specifically autoimmune disease. Methods For this systematic review we carried out a systematic search of four electronic databases (MEDLINE, Embase, CENTRAL, Web of Science) with the two main search terms “autoimmunity” and “ovarian cancer” up to May 10, 2020. We included 36 different autoimmune diseases in our search. From the 4799 screened records, we identified 53 relevant articles for our review, of which 48 were used in our meta-analysis. Results The incidence of ovarian cancer was significantly lower in patients with multiple sclerosis (standardized incidence ratio (SIR) 0.76, 95% CI 0.60 to 0.96). There was a tendency towards a lower risk of ovarian cancer in patients with systematic lupus erythematosus (SIR 0.89, 95% CI 0.68 to 1.15) and a tendency towards a higher risk in those with type 1 diabetes mellitus (SIR 1.49, 95% CI 0.98 to 2.28); however, this was not statistically significant. No conclusions could be drawn on mortality or the influence of immunosuppressive drugs used in the treatment of autoimmune diseases and the incidence of ovarian cancer. Conclusions Our study showed a decreased incidence of ovarian cancer in patients with multiple sclerosis. However, further investigation on the role of the immune system in the development of ovarian cancer in women with autoimmune diseases remains necessary.

A novel alpha-therapy consisting of ²²⁴Ra-labeled calcium carbonate microparticles (²²⁴Ra-CaCO₃-MP) has been designed to treat micrometastatic peritoneal disease via intraperitoneal (IP) administration. This preclinical study aimed to evaluate its efficacy and tolerability when given as a single treatment or in combination with standard of care chemotherapy regimens, in a syngeneic model of ovarian cancer in immune competent mice. Female C57BL/6 mice bearing ID8-fLuc ovarian cancer were treated with ²²⁴Ra-CaCO₃-MP 1 day after IP tumor cell inoculation. The activity dosages of ²²⁴Ra ranged from 14 to 39 kBq/mouse. Additionally, ²²⁴Ra-CaCO₃-MP treatment was followed by either carboplatin (80 mg/kg)-pegylated liposomal doxorubicin (PLD, 1.6 mg/kg) or carboplatin (60 mg/kg)-paclitaxel (10 mg/kg) on day 14 post tumor cell inoculation. All treatments were administered via IP injections. Readouts included survival, clinical signs, and body weight development over time. There was a slight therapeutic benefit after single treatment with ²²⁴Ra-CaCO₃-MP compared to the vehicle control, with median survival ratios (MSRs) ranging between 1.1 and 1.3. The sequential administration of ²²⁴Ra-CaCO₃-MP with either carboplatin-paclitaxel or carboplatin-PLD indicated a synergistic effect on overall survival at certain ²²⁴Ra activities. Moreover, the combinations tested appeared well tolerated in terms of weight assessment in the first 4 weeks after treatment. Overall, this research supports the further evaluation of ²²⁴Ra-CaCO₃-MP in patients with ovarian cancer. However, the most optimal chemotherapy regimen to combine with ²²⁴Ra-CaCO₃-MP should be identified to fully exploit its therapeutic potential.